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Sepsis drug also protects brain cells

19.02.2004

A compound currently used to treat patients with severe sepsis also protects brain cells in an unexpected way, say researchers at the University of Rochester Medical Center in the Feb. 19 issue of the journal Neuron.

Doctors currently use a modified version of activated protein C or APC to reduce inflammation or increase blood flow in patients with severe sepsis, and last year neuroscientist Berislav Zlokovic, M.D., Ph.D., led a team that showed that the compound also protects the cells that are vital to supply blood to the brain. In the latest paper, Zlokovic and colleagues show that the compound also directly protects vital brain cells known as neurons.

While several compounds have been shown in the laboratory to protect neurons, the latest finding is of special interest for a few reasons, says Zlokovic, who heads the Frank P. Smith Laboratories for Neurosurgical Research.

"This is a compound thats naturally present in your body, and its already being used to treat people – its not a chemical tucked away in a laboratory," he says. In addition, one of the biggest side effects of APC is increased bleeding, and the team showed that the protection APC bestows is separate from its ability to increase blood flow and reduce inflammation. The findings open the possibility of creating a new compound that would keep brain cells healthy but without causing major side effects like increased bleeding.

Working closely with Zlokovic, Huang Guo, research assistant professor of Neurosurgery, and Dong Liu, post-doctoral fellow, showed that APC protects neurons by activating receptors known as PAR-1 and PAR-3. They showed that the compound helps protect against a variety of causes of "apoptosis," or programmed cell death, one of the major ways we all lose brain cells.

Preventing neurons from killing themselves – committing apoptosis – when they shouldnt is a broad goal of researchers. Apoptosis often happens when cells detect danger and go into a state of hyper-signaling, much as a panicked airline crew might react as their plane plunges toward the ocean. In the brain, the process results in high levels of chemicals that kill cells and are responsible for a great deal of brain damage from stroke, brain injury, and Alzheimers and Huntingtons diseases.

The team showed that APC protects brain cells from such apoptosis brought about by a variety of causes, as well as apoptosis by a chemical known as staurosporine.

"This opens the door to a new class of anti-apoptotic agents based on blood factors that act directly on neurons" says Zlokovic, who is professor of Neurosurgery. "Regardless of the cause of neuronal apoptosis, neurons are able to survive in the presence of APC."

In a paper last year in Nature Medicine, the team showed that APC protects endothelial cells in the brain – the cells that form blood vessels – by preventing apoptosis of those cells. In the current paper, the team showed both in the laboratory and in mice that APC saved about 70 percent of the neurons that would have otherwise died. The benefit disappears if either PAR-1 or PAR-3 arent working correctly.

In addition to Zlokovic, Guo and Liu, the team from Rochester included Tong Cheng, research assistant professor; technician Rae Insalaco; and Harris Gelbard, professor of neurology. The team also included protein chemist John Griffin and Jose Fernandez of Scripps Research Institute in La Jolla, Calif.

The work was funded by the National Heart, Lung, and Blood Institute and was done in collaboration with Socratech Laboratories, a Rochester start-up company founded by Zlokovic.

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